Natural killer (NK) cell activity during HIV infection: a decrease in NK activity is observed at the clonal level and is not restored afterin vitrolong-term culture of NK cells

Abstract

SUMMARYNK cell activity is impaired in HIV-infected patients. The mechanisms behind the altered NK functions are not clear, and conflicting data concerning NK and antibody-dependent cellular cytotoxicity (ADCC) activity have been reported. In order to investigate whether this impairment is also observed at the clonal level and whether it is related to a defect at the target cell binding and/or the post-binding level, we evaluated highly purified NK cell lines and cloned NK cells obtained from 22 HIV-infected patients at different stages of disease and compared them with normal controls for their ability to: (i) kill K-562 and U-937 cell lines using a 51Cr release assay; (ii) bind and kill K-562 and U-937 cells at the single cell binding level; (iii) release NK cytotoxic factor (NKCF), tumour necrosis factor-alpha (TNF-ax) and interferon-gamma (IFN-y); (iv) kill anti-IgM preincubated Daudi cell line (ADCC activity). This study with cloned NK cells or NK cell lines from HIV-infected individuals showed: (i) a decrease in their lytic capability against target cell lines; (ii) a low ability to form conjugates with K-562 and U-937 cell lines with respect to controls; (iii) a decreased ability to kill bound target cells; (iv) low levels of released NKCF, TNF-a and IFN-y after incubation with U-937 cells. Taken together, these findings suggest that the impaired NK cell function during HIV infection is also observed at the clonal level and is related to defects both at the target and post-binding levels. However, the precise mechanisms remain to be determined. The inability to restore normal NK activity after long-term culture in the presence of high levels of recombinant IL-2 is in agreement with the hypothesis of a 'general anergic process' during HIV infection.

Natural Killer Cell Dysfunction during Acute Infection with Foot-and-Mouth Disease Virus

“…Originally, NK cells were discovered on the basis of their capability to kill certain tumors without prior activation. Now the role of NK cells has been defined in virus infections such as human cytomegalovirus (8,11,55), murine cytomegalovirus virus (2,32), influenza virus (28,35), herpes simplex virus (44,52), ectromelia virus (16,41), and human immunodeficiency virus (HIV) (14,50,56). In two of these infections, a lack or deficiency in NK cell function leads to increased susceptibility to infection (6,10).…”

Indirect activation of rhesus macaque (Macaca mulatta) NK cells in oral and mucosal draining lymph nodes

“…Innate immune cells contribute significantly to the initial response toward invading pathogens, and specifically, natural killer (NK) cells play crucial roles in preventing oral cancers and oral thrush/candidiasis . Interestingly, while systemic NK cell function diminishes with immunodeficiency resulting from HIV or SIV infections, previous work from our laboratory showed little functional differences between oral NK cells from SIV‐infected and uninfected animals when stimulated with mitogens . Unfortunately, artificial stimulation does not recapitulate toll‐like receptors (TLR) activation resulting from pathogen‐associated molecular patterns (PAMPs).…”

“…Unfortunately, artificial stimulation does not recapitulate toll‐like receptors (TLR) activation resulting from pathogen‐associated molecular patterns (PAMPs). TLR expression on NK cells has been a controversial topic, but a consensus in the field suggests that while NK cells may express some TLR, they do not seem to rely directly on TLR engagement in order to respond to an infection or abnormal cell, but more on their environment . Rather antigen‐presenting cells such as dendritic cells (DC), macrophages (MØ) or B cells respond to these signals and indirectly activate the NK cell response.…”

Innate Immune Responses in HIV-Infection

“…The remaining 5% CD16 low/-CD56 high subset produces high concentrations of IFN- and TNF-, but this sub-population exerts a very low cytotoxic potential (Ahmad and Menezes, 1996). In HIV-infected individuals NK cell responses were shown to be impaired and the defects comprised cytotoxic activity of NK cells as well as secretion of CCR5-ligands MIP1 , MIP1 and RANTES (Scott-Algara et al, 1992;Mavilio et al, 2003;Kottilil, 2003). The HIV-mediated impairment of NK cells becomes manifest early after infection and continues during HIV progression and can be attributed to several factors: HIV-infected individuals might have a down-regulation in intracellular perforin and granzyme A stores, which would account for the decreased cytotoxic capacity of NK cells in HIV-infection .…”